PPARgamma is a member of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear hormone receptor (NHR) superfamily of ligand-dependent transcription factors. It plays an important role in a number of pathways including in adipose differentiation, glucose homeostasis, atherosclerosis, and cancer. PPARgamma has a dominant effect in induction of adipose differentiation upon ligand activation. A major portion of this adipogenic activity is regulated by the N-terminal region of PPARgamma, a domain whose function is poorly characterized in PPARgamma and in the nuclear receptor family in general. The N-terminal region is also phosphorylated in response to growth factor stimulation, which in turn modulates PPARgamma activity. The proposed research aims to define and characterize the role of this domain in the regulation of PPARgamma function. Since this region contains adipogenic activity lacking or reduced in other PPAR isoforms, this work will also be important in defining functional specificity between different nuclear receptors that bind to the same DNA sequences. An adipogenic cofactor PGC-2 binds to this region and enhances transcriptional and adipogenic activities of PPARgamma. The function of PGC-2 will be characterized in detail. Secondly, novel factors that bind specifically to the PPARgamma N-terminus that regulate its function will be identified using biochemical methods. In addition, factors that associate with the N-terminus in a phosphorylation-dependent manner will also be isolated.